Ia antigens are membrane-bound glycoproteins (consisting of heterodimers of Class II molecules) encoded for by genes within the Ir (immune response) region of the major histocompatibility complex. These molecules are known to play an important functional role in regulating the immune response to specific antigens. Their close association with antigen recognition, requirement in the cellular interactions that result in an effective immune response, and expression by the cells of the immune system support this classical definition of the immunologic function of Ia. It is not fully appreciated that other roles for Ia may exist, based on its expression by non-lymphoid cells. Although the reticuloendothelial system of most tissues of the body contain cells which bear Ia antigens, it is now known that under both normal and certain pathological conditions Ia antigens are also expressed by a variety of epithelial and endothelial cell types. For example, Ia-positive epidermal cells (keratinocytes) have been observed in individuals with mycosis fungoides, lichen planus, psoriasis, and graft-versus-host disease. Preliminary studies have shown that the expression of Ia by keratinocytes is an inducible phenomenon and appears to be due to keratinocyte synthesis rather than passive absorption of these molecules. Keratinocytes in normal mouse and rat skin that is grafted onto nude mice become Ia-positive shortly after grafting. Furthermore, the keratinocytes of nude mice express Ia following the injection of splenocytes or serum from syngeneic heterozygous and normal mice. These observations suggest that either Ia-positive epithelial cells can play a role in various phases of the immune response or Ia has a much broader function than is currently appreciated. The experiments outlined in this application are designed, using defined in vivo and in vitro assay systems, to: identify the cellular and/or serum factors that induce Ia expression by keratinocytes, determine the origin of the Ia that is expressed by these cells, and correlate this inducible phenomenon with T-cell differentiation, immune responsiveness to specific antigens, and lymphocyte trafficking in response to antigens introduced through the skin.